CN102471259A - 2-amino-2-phenyl-alkanol derivatives, preparation thereof, and pharmaceutical compositions containing same - Google Patents

2-amino-2-phenyl-alkanol derivatives, preparation thereof, and pharmaceutical compositions containing same Download PDF

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CN102471259A
CN102471259A CN2010800339523A CN201080033952A CN102471259A CN 102471259 A CN102471259 A CN 102471259A CN 2010800339523 A CN2010800339523 A CN 2010800339523A CN 201080033952 A CN201080033952 A CN 201080033952A CN 102471259 A CN102471259 A CN 102471259A
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让·帕霍特
克里斯托夫·迪尼
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Oroxcell
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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Abstract

The invention relates to 2-amino-2-phenyl-alkanol-derived esters of general formula (I), where: R1 forms, with R3 and the nitrogen and carbon atoms to which they are respectively attached, a 4- to 7-membered heterocyclic compound, optionally substituted, in position a of the nitrogen atom, by radicals Ra and Rb that, separately from each other, can be a hydrogen or a straight or branched alkyl (1 to 4 C); and R2 is H or a CO-O-CHR4-OCOR5 radical for which R4 is a hydrogen or a straight or branched alkyl (1 to 4 C); and R5 is an alkyl optionally substituted by benzyloxycarbonylamino, acylamino, or by the residue of an amino acid, or is a heterocyclic compound; or R2 is a straight or branched alkyl (1 to 4 C), or an alkyl (2 to 4 C) substituted by OH, alkoxy, alkylthio, NH2, alkylamino, or dialkylamino optionally forming, with the nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic compound, assuming that said substituted alkyl is straight or branched and comprises at least 2 C between >N-R2 and the substituent, wherein, unless otherwise mentioned, alkyl or acyl are straight or branched (1 to 7 C), in the R or S forms thereof or in the form of the mixtures thereof, as well as the pharmaceutically acceptable salts thereof, if present.

Description

2-amino-2-phenyl-alkanol derivatives, its preparation and the pharmaceutical composition that comprises it
Technical field
The present invention relates to 2-amino-2-phenyl-alkanol derivatives, it replaces by different way, and especially is interested in their analgesic activity.The pharmaceutical composition that the invention still further relates to the preparation of these verivates and comprise them.
Background technology
In International Application No. WO 99/01417; (S) 3,4 described, 5-trimethoxybenzoic acid 2-methylamino--2-phenyl-positive butyl ester ((S) 2-methylamino-2-phenyl-n.butyl 3; 4,5-trimethoxy benzoate) and its application in the treatment chronic pain.
In European application EP 1 110 549; Trimebutine [3 has been described; 4; 5-trimethoxybenzoic acid (2-methylamino--2-phenyl) butyl ester PHENRAMINE MALEATE] (trimebutine [(2-methylamino-2-phenyl) butyl 3,4,5-trimethoxybenzoate maleate]) or the application of its steric isomer in treatment inflammatory disease and pain.
British Patent Application GB 1 434 826, described the structure of the ester of alkamine (amino alcohols):
Figure BDA0000133219570000011
Wherein, R 1To R 3Especially can be Wasserstoffatoms, R 4Can be alkyl, R 7Can be alternatively by 1 to 3 substituted aryl of alkoxyl group, and R 5And R 6Represent Wasserstoffatoms, alkyl or aralkyl or with the formed heterocycle of the nitrogen-atoms that they connected.Product can be used as spasmolytic.R has also been described in this Britain's application 7Has structure-NH-R " 7Carbamates.Therefore the aryl carbamates of being formed has analgesia and anti-inflammatory activity.Yet it is very restricted on amine, introducing modification (group), and can not produce the anodyne of strong effect.
Summary of the invention
Find now; The ester derivative class of the 2-amino-2-phenyl-alkanol of following general formula, with its R or S form or their mixture (form), if with and the pharmaceutical salts that exists; Have as the especially interesting activity of anodyne, especially treat chronic pain:
Figure BDA0000133219570000021
Wherein:
R 1With R 3And their nitrogen of connecting respectively and carbon atom form and have 4 to 7 yuan of heterocycles, at the alpha position of this nitrogen-atoms alternatively by one or two R aBase and R bBase replaces, R aBase and R bBase is independently of one another, can be the alkyl that comprises 1 to 4 carbon atom of hydrogen or straight or branched, and
R 2Be Wasserstoffatoms or represent CO-O-CHR 4-OCOR 5Base, wherein R 4Be the alkyl that comprises 1 to 4 C of Wasserstoffatoms or straight or branched, and R 5Be amino by benzyloxycarbonyl alternatively, carboxamido-group or by the substituted alkyl of amino acid whose residue, perhaps represent heterocyclic radical or
R 2Represent the alkyl that comprises 1 to 4 C of straight or branched, by OH, alkoxyl group, alkyl sulfide, NH 2, alkylamino or substituted 2 to 4 C of dialkyl amido alkyl; Nitrogen-atoms that the moieties of dialkyl amido can be connected with them forms 5-or 6-member's heterocycle, the alkyl that should understand said substituted 2 to 4 C be straight or branched and have R at this 2Nitrogen-atoms and substituting group between comprise at least 2 C atoms;
Should be understood that unless otherwise indicated, alkyl or acyl group or residue (remainders) be straight or branched and to comprise 1 to 7 carbon atom, especially acyl group can be ethanoyl.Aryl or aralkyl can be to comprise 6 to 10 yuan of lists or bicyclic, for example phenyl, naphthyl, benzyl, styroyl or naphthalane base (naphthylalkyl).
Should be understood that heterocyclic radical can be the group of list or dicyclo, aromatic or non-aromatic, comprise 5 to 10 members and comprise 1 to 4 heteroatoms that is selected from oxygen, nitrogen or sulphur.Especially they can be selected from thienyl; Furyl; Pyrryl; Pyrrolidyl; Piperidyl; Pyridyl; Pyrazinyl; Pyrimidyl; Pyridazinyl; Piperazinyl; Dioxa cyclopentenyl (dioxolyl); Imidazolyl; Imidazolinyl; Pyrazolyl; Tetrazyl; Pyranyl (pyrannyl); THP trtrahydropyranyl (tetrahydropyrannyl); Tetrahydrofuran base (tetrahydrofuranyl) oxazolyl; Thiazolyl; Thiazinyl; Morpholinyl; Thiomorpholine (thiomorpholinyl); Indyl; Indolizinyl (indolizinyl); Quinolyl; Naphthyridinyl (naphthyridinyl).
Should be understood that the above amino acid of mentioning especially can be to be selected from natural or non--natural amino acid, as, with glycocoll, L-Ala, leucine, Isoleucine, proline(Pro), Xie Ansuan, phenylalanine(Phe) or the H of L or D 2NC (CH 3) 2CO 2H, and these groups were protected with the form of amides or carbamates before building-up reactions; The protection of protection base and discharge according to by T.W. Greene and P.G.M.Wuts at Organic Synthesis, the method described in the 4th Edition ISBN 978-0-471-69754-1, December 2006 is carried out.
Halogen atom is selected from chlorine, fluorine, bromine and iodine.
According to the preferred embodiment of the present invention, alkyl or acyl group are straight or brancheds, and comprise 1 to 4 carbon atom.
According to the present invention, the ester derivative of the 2-amino-2-phenyl-alkanol of general formula (I) is by the prepared in reaction of the verivate of the 2-amino-2-phenyl-paraffin alcohols of the verivate of following general formula (II) and following general formula (III):
Figure BDA0000133219570000041
Wherein, Z be halogen atom, hydroxyl or active ester rest part (residue, remainder), R wherein 1And R 3Defined like the front, R 2Defined like the front, if suitably, at R 2When being Wasserstoffatoms, the replacement of the amine of the ester derivative of the 2-amino-2-phenyl-alkanol of the following general formula that then carries out being obtained:
Wherein, R 1And R 3Like above definition,
Perhaps, obtain R in expectation 2Be-CO-O-CHR 4-OCOR 5Verivate the time, through the effect of chloroformic acid chlorine alkyl ester, then cesium salt, product that is obtained and respective acids R 5The basic salt of COOH, sodium salt for example, sylvite or also can be this sour silver salt or quaternary ammonium salt (for example tertiary butyl ammonium salt) reaction,
Perhaps, obtain R in expectation 2When being alkyl-substituted derivatives,, then, amide form is reduced to amine through acidylate by the active ester of carboxylic acid halides or structure (V):
R 2-CO-Z (V)
Wherein, R 2As defined above, and Z be halogen atom or active ester rest part (residue, reminder).
The product of general formula (II) can be 3,4, and the reactive derivative of 5-trimethoxybenzoic acid is like carboxylic acid halides or active ester.
The reaction of the verivate of the 2-amino-2-phenyl-paraffin alcohols of general formula (III) preferably utilizes R 2The verivate that is Wasserstoffatoms carries out.
Product at general formula (II) is 3; 4; When the reactive derivative of 5-trimethoxybenzoic acid such as carboxylic acid halides or active ester; Under the situation of the carboxylic acid halides of general formula (II), the reaction of the verivate of the 2-amino-2-phenyl-paraffin alcohols of the verivate of general formula (II) and general formula (III) is advantageously carried out under the condition that nitrogenous base (like triethylamine, Dimethylamino pyridine, diisopropylethylamine) exists, and reaction is usually in organic solvent such as chlorinated solvent (for example dichloromethane, ethylene dichloride, chloroform); Carry out being contained under 0 to 70 ℃ the temperature, preferably in nitrogen (atmosphere) operation down.And under the situation of the active ester of general formula (II), be reflected at the existence that is present in the sodium methylate in the organic solvent (like toluene) and alcohol as under methyl alcohol or the alcoholic acid existence condition, carry out being contained under 25 to 150 ℃ the temperature.
When Z is halogen atom, advantageously be selected from chlorine or bromine.
Product at general formula (II) is 3,4, during the 5-trimethoxybenzoic acid, reaction usually in halogenated solvent (for example dichloromethane, ethylene dichloride, chloroform) under the condition that carbodiimide exists, carry out being contained under 0 to 70 ℃ the temperature.
Should be understood that when expectation obtains the verivate with the general formula (IV) of R or S form, react with the verivate of the 2-amino-2-phenyl-paraffin alcohols of the general formula (III) of R or S form.Should also be understood that the verivate with the general formula (IV) of R or S form produces the verivate with the general formula (I) of R or S form.
Obtain wherein R in expectation 2Base is-CO-O-CHR 4-OCOR 5Product the time; The reaction of the product through chloroformic acid chlorine alkyl ester and general formula (IV) is operated; This is reflected at organic solvent such as chlorinated solvent (for example methylene dichloride, ethylene dichloride), or as in the ether (for example THF), is being contained under the temperature between-10 to 50 ℃ and is carrying out.Then be product and the respective acids R that is obtained 5The basic salt of COOH, in organic solvent, under Soiodin existence or non-existent condition, the reaction under the temperature between 0 to 60 ℃, wherein respective acids R 5The basic salt of COOH is sodium salt, sylvite or cesium salt, silver salt or quaternary ammonium salt for example, and organic solvent such as amides be N, chlorinated solvent (for example methylene dichloride), ester (for example ETHYLE ACETATE), aryl hydrocarbon (for example toluene), nitrile (for example acetonitrile), ketone (for example acetone, methyl ethyl ketone) for example.With the mode of instance, R therein 1And R 3Form under the situation with 5 yuan of rings with nitrogen-atoms and R therein 2Be-CO-O-C (CH 3)-O-CO-CH 2NHCOCH 3Situation under, product can be through the preparation of following scheme:
Figure BDA0000133219570000061
Obtain wherein R in expectation 2When being the verivate of general formula (I) of substituted alkyl, the acylation reaction of the amine of the verivate of general formula (IV) is carried out under the temperature that is contained between 0 to 70 ℃ in halogenated solvent (for example methylene dichloride, ethylene dichloride) or in ether (THF).If suitable, utilize hydroxybenzotriazole to prepare active ester.Under the condition of borane or aluminium and lithium hydride existence, in THF, under the temperature that is contained between 0 to 70 ℃, reduce.
3,4 of general formula (II), the verivate of 5-trimethoxybenzoic acid can be according to the ordinary method preparation that is used for carboxylic-acid is converted into their reactive derivative, and this method does not change the residue of molecule.
2-phenyl-tetramethyleneimine-2-carboxylic acid, the precursor of the alcohol of general formula (III) is a commerical prod, its verivate can prepare through the compound method that is similar to this product.
More particularly, respective acids can according to or through being similar at A.O.Martiryosyan S.P.Gasparyan et al., Chemistry of Heterocyclic Compounds, vol. 36(4), the compound method preparation described in the 416-420 (2000), and especially according to following scheme:
This is at R 2Be hydrogen, and the R of formula (III) 1And R 3Annular form with them representes to have substituent R aAnd R bThe time,
Perhaps, at R 2Not Wasserstoffatoms, and the R of formula (III) 1And R 3Be expressed as and have substituent R aAnd R bAnnular form the time, according to following scheme (diagram):
Figure BDA0000133219570000081
Should be understood that the alkali that uses in the fs can be tertiary amine, like triethylamine or diisopropylethylamine, and coupling agent can be, for example 1-Hydroxy Benzotriazole.
Usually, the verivate of general formula (III) can be through being reduced to alcohol with respective acids, and prepare through the method that is similar to described in patented claim FR 2 765 218 or the EP 510 168.With the mode of instance, according to following scheme:
Should be understood that when intention obtains the product with the general formula (I) of S or R form, react with the verivate of the 2-amino-2-phenyl-paraffin alcohols of the general formula (III) of S or R form.
Verivate with the 2-amino-2-phenyl-paraffin alcohols of the general formula (III) of S or R form can prepare through separating according to the ordinary method (this method does not influence the residue of molecule) that is used for enantiomer separation; Or through being similar to the method preparation described in the European patent EP 510,168.
When there is pharmaceutical salts in they, can be additive salt with acids.Especially, with the salt of mineral acid, for example hydrochloride class, hydrobromide class, Sulfates, phosphoric acid salt, or with organic acid additive salt, for example acetate salt, maleic acid salt, fumaric acid salt, tartrates, citric acid salt.
The verivate of general formula (I), purifying especially passes through chromatography or crystallization process according to conventional methods.
Because their strong analgesic activities of imitating, especially for chronic pain, the verivate of general formula (I) is especially available.
Their activity passes through to adopt G.B.Brown, 3H-batrachotoxinin-A benzoate binding to voltage-sensitive sodium channels:inhibition by the channel blockers tetrodotoxin and saxitoxin, J.Neurosci., 6, the method in 2064 (1986) suppresses proof in the test external in the sodium channel.In this vitro test, product according to the present invention demonstrates the inhibition activity between 25 to 90% with the concentration of 3.2 (μ M).
This activity is the analgesic activity of predictive, and therefore has the likely effectiveness that is used to treat Encelialgia and neuropathic pain: Roman F.J.et al., J.Pharmacol.Exp.Ther., 289 (3), 1391-97 (1999); V.Kayser et al., Life Sciences, 66 (5), 433-39 (2000).
The vital role of sodium channel in nociception obtains following document and extensively supports: Wood J.N.et al., Voltage-gated sodium channels and pain pathways, J.Neurobiol., 61 (1), 55-71 (2004); Cox JJ.et al., Nature; 444 (7121), 894-8 (2006); Ahmad S.et al., Hum.Mol.Genet., 16 (17), 2114-21 (2007).More particularly extensively known, the treatment potentiality in the treatment neuropathic pain of sodium channel suppressor factor: Devor M., Sodium channels and mechanisms of neuropathic pain., J.Pain., 7 (1 Suppl 1), S3-S12 (2006).Up to now, a large amount of synthetic products prove that the sodium channel suppressor factor can be increased in the interests/risk distribution of the medicine that uses in the treatment pain: Veneroni et al., Pain., 102 (1-2), 17-25 (2003); Oket al., Bioorg.Med.Chem.Lett., 16 (5), 1358-61 (2006); Ilyin et al., J.Pharmacol.Exp.Ther., 318 (3), 1083-93 (2006); Jarvis et al., Proc.Natl.Acad.Sci.USA., 104 (20), 8520-5 (2007).
And, do not demonstrate known toxicity according to product of the present invention.
In the product of general formula (I), more specifically useful product is such: R wherein 1With R 3And their nitrogen of connecting respectively and carbon atom form and have 4 to 7 yuan of heterocycles, at the alpha position of this nitrogen-atoms alternatively by one or two R aBase and R bBase replaces, R aBase and R bBase is independently of one another, can be the alkyl that comprises 1 to 4 carbon atom of Wasserstoffatoms or straight or branched, and R 2Be Wasserstoffatoms, and in these products, the ester derivative of the 2-amino-2-phenyl-alkanol of general formula (I) especially, with its R or S form or its mixture (form), if with and any pharmaceutical salts that exists, wherein R 1With R 3And their nitrogen-atoms of connecting respectively and carbon atom form together and have 4 to 7 yuan of heterocycles, and R 2It is Wasserstoffatoms.
More specifically preferably below listed product:
3,4,5-trimethoxy-phenylformic acid 2-phenyl-azetidine (azetidin)-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 4-methyl-2-phenyl-azetidine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 4,4-dimethyl--2-phenyl-azetidine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 2-phenyl-tetramethyleneimine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 5-methyl-2-phenyl-tetramethyleneimine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 5,5-dimethyl--2-phenyl-tetramethyleneimine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 2-phenyl-piperidines-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 6-methyl-2-phenyl-piperidines-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 6,6-dimethyl--2-phenyl-piperidines-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 2-phenyl-nitrogen heterocyclic heptan (azepan)-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 7-methyl-2-phenyl-nitrogen heterocyclic heptan-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 7,7-dimethyl--2-phenyl-nitrogen heterocyclic heptan-2-base methyl esters.
Embodiment
Following embodiment explains the present invention.
In following embodiment, the implication of employed abbreviation is following:
DMF N (dimethylformamide)
DMSO DMSO 99.8MIN. (dimethylsulphoxide)
THF THF (tetrahydrofuran)
DIPEA N, and the N-diisopropylethylamine (N, N-diisopropylethylamine)
TLC thin-layer chromatography (thin layer chromatography)
Embodiment
Figure BDA0000133219570000111
In the three-necked flask that distillation bend pipe (distillation bend) is installed, (2-phenylpyrrole alkyl-2-yl) methyl alcohol of 200mg (0.001mol) is dissolved in the ethanol of toluene and 0.4ml of 6ml.With 3,4 of 0.026g (0.00124mol), 5-trimethoxy-oil of Niobe is added to this reaction mixture.Reaction mixture is heated to 130 ℃, adds the sodium methylate of 61mg (0.0011mol) then.Reaction mixture is spent the night 130 ℃ of indwellings, and methyl alcohol is distillated.Add 3,4 of other 0.0266g, 5-trimethoxy-oil of Niobe heats reaction mixture 3 hours at 130 ℃ then.
On silicon-dioxide, (carry out) TLC (CH 2Cl 2/ MeOH:95/5) show that this reaction accomplishes.
Reaction mixture carries out purifying: CH on silica column 2Cl 2/ MeOH:99/1, to produce 3,4 of 54mg, 5-trimethoxy-phenylformic acid 2-phenyl-pyrrolidyl-2-base methyl esters is the form (productive rate: 10%) of yellow oil.
NMR?1H(300MHz，CDCl3)：δ(ppm)＝1.56-2.17(m，4H，CH2)；2.96-3.15(m，2H，CH2N)；3.76-3.91(3(s)，9H，OCH3)；4.33(dd，2H，CH2O)；7.08(s，2H，ArH)；7.24-7.35(m，3H，ArH)；7.43-7.55(d，2H，ArH).
MS(ES+)：[M+H]+，m/z：372.2
2-phenylpyrrole alkyl-2-base methyl alcohol can prepare with following method:
Under nitrogen atmosphere, with 2-phenyl-pyrrolidyl-2-carboxylic acid (217.20mg, 0.0011358mol) be dissolved in THF (THF) (5ml) in.Drip the solution of the 1M borane-THF mixture of 2.3mL in THF.With this reaction mixture reflux 3 hours, in ice bath, cool off then.
The NaOH solution of the 5M of Dropwise 5 mL.Water is with twice of the dichloromethane extraction of 20mL.The organic phase that obtains is used Na 2SO 4Drying is filtered and concentrate drying in Rotary Evaporators then.By this way, obtain 2-phenylpyrrole alkyl-2-base methyl alcohol of 200.0mg, be yellow oil form (productive rate: 99%)
NMR?1H(300MHz，CD3OD)：δ(ppm)＝1.64-2.17(m，4H，CH2)；2.80-3.08(m，2H，CH2N)；3.21(m，1H，NH)；3.42-3.58(m，2H，CH2O)；3.61(m，1H，OH)；7.08-7.43(m，5H，ArH)。
The product of general formula (I) can oral administration, parenteral route, through tongue or rectum path, with aerosol or with the localized forms administration.
The invention still further relates to comprise at least a general formula (I) if the medicinal compsns of salt of ester derivative and/or their any existence of 2-amino-2-phenyl-alkanol, with pure form or with the form of one or more compatible and medicinal thinners or adjuvant combination.
These compsns can exist with the form of solids compsn; Especially with tablet, coating tablet, pill, capsule, pulvis or particle to put into solution or suspension-s; Or with forms of liquid compositions such as injection solution or suspensoid, drinkable solution or suspension, syrup, emulsus agent, comprise the elixir of inert diluent such as water or Yellow Protopet 2A; Or with the form of suppository, ointment, ointment and lotion, or can also be with the form of spray composite.Prepare these medicinal forms according to conventional methods.
Be used for the solids compsn of orally give; Active ingredient according to the present invention mixes with one or more inert diluents or adjuvant, for example sucrose, lactose, starch or its verivate, Microcrystalline Cellulose, colloid silica, polyvidone, talcum, Sudan Gum-arabic.
These compsns can also comprise for example lubricant of material except thinner, like Magnesium Stearate or be intended to the dressing of sustained release.
Be used for pharmaceutical composition for oral administration, can comprise aqueous carrier or non-aqueous carrier such as thinner, and can also comprise that other materials are for example moistening, sweetening or seasoning product.Non-aqueous composition can comprise fatty substance, paraffin derivative, glycols, the soybean lecithin in animal or plant source.
The compsn of parenteral administration is more especially can be with the compsn of intramuscular or intravenous route administration.The compsn that is used for parenteral administration can be sterile solution or emulsus agent.Below can be used as solvent or carrier: Ucar 35, polyoxyethylene glycol, vegetables oils, especially sweet oil, injectable organosilane ester be OE for example.
These compsns can also comprise adjuvant, especially wetting agent, isotonic agent, emulsifying agent, dispersion agent, stablizer and/or sanitas.
Sterilization can be carried out with several kinds of modes, for example utilizes the bacteriology filtration, passes through irradiation or passes through heating.Said composition can also be with the prepare of aseptic solid composite, and it is dissolved in the aqua sterilisa or any other injectable sterile medium in use.
The compsn that is used for rectal administration is suppository or rectal capsule, and it also comprises vehicle such as theobroma oil, semi-synthetic glyceride type or Zusoplast 9002 class except active ingredient.
Being used for topical drug delivery composition can be, patch (patch, ointment) for example, and it also comprises compatible vehicle such as silicone oil, paraffin except active ingredient.
Compsn can also be an aerosol.Use for the form with the liquid aerosol, compsn can be stable sterile solution or be dissolved in the solids compsn in apyrogenic (apyrogenic) aqua sterilisa, serum or any other pharmaceutical carrier in use.In order to use with the form that is intended to the direct dry aerosol that sucks; Make up with the active ingredient porphyrize and with thinner or water-soluble solid carrier; Wherein thinner or water-soluble solid carrier have the size distribution of 30 to 80 μ m, for example VISOSE, N.F,USP MANNITOL or lactose.
In the human treatment, the doctor will determine that he estimates for the optimal dosage of treatment, other factors that it depends on age, body weight or is fit to patient to be treated.According to waiting to treat the routine dose that the patient can change with the disease of suffering from, can be, for example, for the adult, oral administration path, 50mg to 2g every day.
Following embodiment explanation is according to compsn of the present invention.
Embodiment
Preparation that can the oral administration administration utilizes following component to prepare:
3,4, the 2-phenyl-pyrrolidyl of 5-trimethoxybenzoic acid-2-base methyl esters ... 100mg
Spherolac 100,
Modified corn starch,
HPMC,
Sodium Hydroxymethyl Stalcs,
Tartrate,
Colloid silica,
Magnesium Stearate,
Macrogol 4000 (macrogol 4000),
Titanium oxide.

Claims (6)

1. the ester derivative of the amino of the 2-of general formula below a kind-2-phenyl-alkanol, with its R or S form or their mixture, if with and the pharmaceutical salts that exists:
Wherein:
R 1With R 3And their nitrogen of connecting respectively and carbon atom form and have 4 to 7 yuan of heterocycles, at the alpha position of said nitrogen-atoms alternatively by one or two R aBase and R bBase replaces, said R aBase and R bBase is independently of one another, can be the alkyl that comprises 1 to 4 carbon atom of Wasserstoffatoms or straight or branched, and
R 2Be Wasserstoffatoms or represent CO-O-CHR 4-OCOR 5Base, wherein R 4Be the alkyl that comprises 1 to 4 C of Wasserstoffatoms or straight or branched, and R 5Be amino by benzyloxycarbonyl alternatively, amido or, perhaps represent heterocyclic radical by the substituted alkyl of amino acid whose residue, or
R 2Represent the alkyl that comprises 1 to 4 C of straight or branched, by the substituted alkyl that comprises 2 to 4 C of hydroxyl, alkoxyl group, alkylthio, amino, alkylamino or dialkyl amido; Nitrogen-atoms that the moieties of said dialkyl amido can be connected with them forms 5 or 6 yuan of heterocycles, should understand the said substituted alkyl that comprises 2 to 4 C and be straight or branched and having R 2Said nitrogen-atoms and substituting group between comprise at least 2 C, unless otherwise indicated, said alkyl or acyl group be straight or branched and comprise 1 to 7 carbon atom.
2. the ester derivative of 2-amino according to claim 1-2-phenyl-alkanol is characterized in that, with its R or S form or their mixture, if with and the pharmaceutical salts that exists,
R 1With R 3And their said nitrogen-atoms of connecting respectively and carbon atom form and have 4 to 7 yuan of heterocycles, at the alpha position of said nitrogen-atoms alternatively by one or two R aBase and R bBase replaces, said R aBase and R bBase can be alkyl hydrogen or straight or branched and that comprise 1 to 4 carbon atom independently of one another, and R 2It is Wasserstoffatoms.
3. according to the ester derivative of claim 1 or 2 each described 2-amino-2-phenyl-alkanols, it is characterized in that, with its R or S form or their mixture, if with and the pharmaceutical salts that exists, R 1With R 3And their said nitrogen-atoms of connecting respectively and carbon atom form together and have 4 to 7 yuan of heterocycles, and R 2It is Wasserstoffatoms.
4. according to the ester derivative of claim 1 or 2 each described 2-amino-2-phenyl-alkanols, it is characterized in that in its corresponding following structure one:
3,4,5-trimethoxy-phenylformic acid 2-phenyl-azetidine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 4-methyl-2-phenyl-azetidine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 4,4-dimethyl--2-phenyl-azetidine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 2-phenyl-tetramethyleneimine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 5-methyl-2-phenyl-tetramethyleneimine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 5,5-dimethyl--2-phenyl-tetramethyleneimine-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 2-phenyl-piperidines-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 6-methyl-2-phenyl-piperidines-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 6,6-dimethyl--2-phenyl-piperidines-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 2-phenyl-nitrogen heterocyclic heptan-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 7-methyl-2-phenyl-nitrogen heterocyclic heptan-2-base methyl esters
3,4,5-trimethoxy-phenylformic acid 7,7-dimethyl--2-phenyl-nitrogen heterocyclic heptan-2-base methyl esters.
5. method that is used to prepare verivate according to claim 1; It is characterized in that; The derivatives reaction of the 2-amino-2-phenyl-paraffin alcohols of the verivate of following general formula (II) and following general formula (III) is if be converted into the pharmaceutical salts that it exists with the product that obtains then alternatively
Wherein, Z is the rest part of halogen atom, hydroxyl or active ester,
Figure FDA0000133219560000032
R wherein 1And R 3Such as in claim 1 definition, and R 2Defined like the front, if suitably, at R 2When being Wasserstoffatoms, the amine of the ester derivative of the 2-amino-2-phenyl-alkanol of the following general formula that obtained is replaced:
Figure FDA0000133219560000033
Wherein, R 1And R 3Like above definition,
Perhaps, obtain wherein R in expectation 2Be-CO-O-CHR 4-OCOR 5Verivate the time, through the effect of chloroformic acid chloro alkyl ester, then, product that is obtained and respective acids R 5The basic salt of COOH, or also can be the reaction of this sour silver salt or quaternary ammonium salt,
Perhaps, obtain wherein R in expectation 2When being substituted alkyl, the acidylate through by the active ester of carboxylic acid halides or structure (V) then is reduced to amine with amide form,
R 2-CO-Z (V)
Wherein, R 2As defined above, and Z is the rest part of halogen atom or active ester.
6. pharmaceutical composition that comprises at least a product according to claim 1, with pure state or with the form of one or more compatible and medicinal thinners or adjuvant combination.
CN2010800339523A 2009-07-30 2010-07-28 2-amino-2-phenyl-alkanol derivatives, preparation thereof, and pharmaceutical compositions containing same Pending CN102471259A (en)

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